HYPOKINETIC MOVEMENT DISORDERS
PARKINSON DISEASE (PD)
Introduction: Most common neurodegenerative mvt d/o affecting ˜1% of people >60. Men:Women 3:2 predominance (unclear why), mean onset 60 yo (range: 40-70). Course variable. Primarily sporadic dz, but several familial forms identified. To date, 18 genes identified that can cause early-onset (<40) familial dz or late-onset familial dz or predispose to sporadic dz. Routine genetic screening not recommended.
Pathophysiology: Pathologic hallmark: Degeneration of dopaminergic nigrostriatal projection neurons. Loss of pigmented neurons in substantia nigra & other pigment nuclei (more widespread pathology identified). Lewy bodies (eosinophilic cytoplasmic inclusions) → composed of alpha-synuclein (normally found in unfolded form, but in Lewy bodies, high concentrations aggregate as filaments) and ubiquitin.
Clinical features/dx
Diagnostic criteria: Cardinal features are rest tremor, bradykinesia, rigidity, and postural instability w/asymmetric onset. Features pointing to an alternate dx are early (<3 yr) prominent instability/falls, early (<3 yr) freezing, early (<3 yr) hallucinations, dementia preceding motor symptoms or in 1st yr; supranuclear gaze palsy; symptomatic dysautonomia; documented condition known to cause parkinsonism, e.g., drugs. Definite dx only w/autopsy.
Other features: 40% develop dementia → see chapter Dementia for dementia w/Lewy bodies. ANS → bowel/bladder dysfxn, orthostatic hypotension.
Differential dx: (1) Parkinson-plus syndromes: eventually diagnosed in about 25% of pts w/original dx of PD. Clues that may not be PD: early dementia → Lewy body dz, early/frequent falls → PSP, orthostatic hypotension → MSA, apraxia/alien hand → CBD, rapid onset → structural lesion/toxins. Typically have POOR response to dopaminergic therapy; worse prognosis; more rapid progression. (2) Drug-induced or tardive parkinsonism: reversible (may take months), found to cause 20% of PD in one study; consider this if rapid onset of PD sx occurs; drugs that cause it → antipsychotics, antiemetics, amiodarone, valproate, lithium, Ca+ channel blockers. (3) Structural: tumor, hydrocephalus, chronic subdural hematoma, trauma, vascular (Binswanger dz = multiple lacunar infarcts in basal ganglia leading to parkinsonism w/LE predominant symptoms). (4) Infectious: postencephalitic, prion dz, HIV/AIDS, PML, neurosyphilis, SSPE. (5) Toxic: carbon monoxide, carbon disulfide, manganese, MPTP, rotenone, paraquat. (6) Metabolic/miscellaneous: hepatocerebral degeneration, hypoparathyroidism/pseudohypoparathyroidism, hypoxia, Wilson dz, hypocalcemia (Fahr dz).
Rx
L-dopa-carbidopa: Most effective med, active w/in 30 min of med ingestion, doesn’t help all sxs (particularly postural instability). Starting med early in dz doesn’t ↓ long-term efficacy. Start 25/100 mg tid. Titrate up by 1 pill qd or qod to achieve clinical effect. Should taper up to at least 1 g/day for 3 mo → if no improvement,
consider atypical PD or other d/o (only 10% of path proven PD have no response to med). If d/c, taper slowly as abrupt cessation can cause hyperpyrexia/rigidity or neuroleptic malignant syndrome (NMS).
Side effects: Nausea (common w/med initiation) → give med w/meal or crackers (but high-protein meal decreases med absorption) or add additional carbidopa. Dyskinesias (worsen as dz progresses), vivid dreams, sleep disturbance, visual hallucinations, hypotension, constipation, compulsive behavior (e.g., gambling).
Carbidopa: ↓ peripheral side effects of L-dopa (nausea/hypotension). Daily dose of 75 mg needed; can increase as needed.
Dopamine agonists: Less efficacious than L-dopa but still first-line alternative. Thought to ↓ risk (by 3-4×) of dyskinesias/motor fluctuations in the first 5 yr of tx vs. L-dopa. Ergot derivatives (pergolide) associated w/valvular dz, nonergots preferred (e.g., pramipexole & ropinirole). Side effects: Decreased impulse control → gambling, hypersexuality, hypomanic states. Confusion, somnolence, delirium, hallucinations that are more common in elderly. Peripheral edema.
MAO-B inhibitors (rasagiline, selegiline): Reduce dopamine metabolism. Weakly effective meds but may increase effectiveness (and side effects) of L-dopa. Controversial evidence that rasagiline is neuroprotective. Side effects: Nausea, headache. Insomnia, confusion w/selegiline. Avoid w/SSRI, TCA, or MAO-B inhibitors that can cause serotonin syndrome.
COMT inhibitors: Prolong levodopa effect and reduces “wearing off.” Give entacapone w/each dose of L-dopa. Avoid use of tolcapone given liver toxicity, needs LFT monitoring.
Anticholinergics: Reduce tremor. Use limited by confusion (especially in pts >70).
Amantadine: Weakly effective monotherapy. May reduce dyskinesias/motor fluctuations due to levodopa.
Atypical antipsychotics (quetiapine, clozapine): For PD-associated psychosis.
Which medication to start? Most pts will need dopaminergic tx. If tremor is a major sympt, try anticholinergic or amantadine monotherapy. Dopamine agonist vs. l-dopa: L-dopa associated w/increased motor complications (i.e., dyskinesia, mtr fluctuations) early in Rx (<5 yr) but has better overall motor fxn. Controversy over whether early L-dopa tx has long-term consequences for motor fluctuations. Some evidence that motor complications in the two grps equalize over time (10-14 yr). Eventually those treated w/agonist will require adjunctive L-dopa. (NEJM 2000;342:1484; J Neurol Neurosurg Psych 1994;57:1034; Neurology 2008;71:474; Lancet 2014;14:60683).
Neuroprotection: Debate if L-dopa is neurotoxic or neuroprotective. Controversial evidence that rasagiline (TEMPO, ADAGIO studies) may be neuroprotective. Ongoing studies on uric acid. No clear evidence for Coenzyme Q10, riluzole, and agonists.
Surgery: Indicated in pts who were L-dopa responsive but developed motor fluctuations/dyskinesias, intractable tremor, dystonia. Benefits of surgery rarely exceed original drug effect. DBS currently preferred over ablation (such as pallidotomy or thalamotomy) used in 50 s. Two major targets for DBS: globus pallidus internus (GPi) and subthalamic nucleus (STN). DBS improves motor fxn (“on time” w/o motor fluctuations) and QOL. May have adverse cognitive and mood effects.
Long-term medication complications
Motor fluctuations: Wearing off between doses, often predictable. Linked to low plasma levels of meds. As dz progresses, brain DA levels are more dependent on plasma levels. Tx: (1) Advise to avoid taking L-dopa w/high-protein meals; tighten dose interval (more frequent doses at same dose). (2) Add COMT inhibitors: ↑ half-life of L-dopa. (3) MAO-B inhibitors: ↓ dopa breakdown in CNS (selegiline, rasagiline). (4) DBS if above fails.
Dyskinesia: Involuntary choreiform mvmts, often linked to high plasma dopamine levels. As PD progresses, dyskinesia occurs at lower L-dopa/agonist doses. Cause unclear; exogenous dopaminergic stim in denervated striatum contributes. At 5 yr, ˜11% risk of dyskinesia, ˜10 yr 33%, >10 yr ˜90%. Tx: Reduce L-dopa dose, switch from controlled release to immediate release, switch to dopa agonist monotherapy (if tolerated), or add amantadine (NMDA receptor antag) or clozapine (Neurology 2004;62:381).
What to do in the inpatient setting
Continue home meds if possible. Even if NPO for surgery, continue meds until morning of surgery unless clear contraindication. Most meds NOT available in IV form. Sx will worsen if meds held. Other illnesses can also worsen PD symptoms.
MULTIPLE SYSTEMS ATROPHY (MSA)
Introduction: Progressive dz w/autonomic dysfxn +/- parkinsonian, cerebellar si/sx, pyramidal sympts. Less common features: dystonia, dyskinesias, chorea. Cognition relatively preserved. Two types: MSA-P (prominent parkinsonism), MSA-C (prominent cerebellar sympts). Sporadic dz, prevalence ˜3/100 K, M > F, average onset 55 yo (range 30-80 s), early disability (˜3-5 yr), mean survival ˜6-10 yr.
Pathology: Alpha-synucleinopathy w/glial cytoplasmic inclusions of alpha-synuclein. ANS sx → cell loss in brainstem (PRF, dorsal motor vagus nucleus) + spinal cord (parasympathetic preganglionic for bladder/sexual, intermediolateral column for hypotension). MSA-P → striatonigral system atrophy. MSA-C → olivopontocerebellar atrophy.
Clinical manifestations
Autonomic: Occurs in all patients. Orthostatic hypotension is symptomatic in 70%; recurrent syncope in 15%; l-dopa may worsen it. Urogenital sxs (80%): Urinary retention/incontinence, early erectile dysfxn.
MSA-P (parkinsonism, prev. known as striatonigral degeneration, or SND): Parkinsonism is main feature in 80% of pts. Progressive akinesia/bradykinesia, rigidity, postural instability. Irregular, myoclonic (jerky) tremor > rest tremor. Orofacial or craniocervical dystonia anterocollis and laryngeal stridor common, w/quivering high-pitched dysarthria.
MSA-C (cerebellar, prev. known as olivopontocerebellar atrophy, or OPCA): Occurs in ˜20%. Gait/limb ataxia, scanning dysarthria, cerebellar oculomotor problems. If + FH consider SCA & not MSA.
Imaging: MRI w/putaminal, olivopontocerebellar atrophy. T2 hyperintensities in pons, midcerebellar peduncles— > “Hot cross bun” sign due to cruciform degeneration of pontocerebellar fibers. GRE (gradient echo) hypointensity in putamen ± slit-like hyperintense rim around putamen (latter related to gliosis). ADC → ↑ signal in putamen (due to degeneration), not seen in PD, but seen w/PSP.
Rx
Parkinsonism: 30% initially responsive to L-dopa but usually require higher dose (up to 1,000 mg qd) and response declines over time; dopamine may worsen orthostatic hypotension and induced confusion. Botulin toxin for dystonia.
Orthostatic hypotension: Avoid large meals, increase salt intake, avoid straining during urination/defecation, no EtOH/drugs, elastic stockings, head up tilted bed. Fludrocortisone (up to 0.2 mg qd) or midodrine (up to 15 mg tid) first line. Pyridostigmine (up to 60 mg tid) has slight benefit and does not worsen supine HTN. Droxidopa newly approved medication (start 100 mg tid → up to 1,800 mg daily). If supine HTN: give meds for hypotension > 3 h before bed, treat only if SBP >200, start nighttime short-acting Ca2+ antagonist. Impotence → penile injections (prostaglandin), sildenafil (but can worsen hypotension). Speech/bulbar dysfxn: Inspiratory stridor can develop; monitor for sleep apnea.
PROGRESSIVE SUPRANUCLEAR PALSY (PSP)
Introduction: Progressive dz w/vertical gaze difficulties & falls/gait instability w/in first year of onset. Prevalence ˜2/100 K; 5% of pts in mvmt d/o clinic have PSP; no gender difference; average onset ˜60.
Pathology: Tauopathy. Globose neurofibrillary tangles (tau deposits) in the brainstem & basal ganglia. Definitive dx via autopsy.
Clinical features
Parkinsonism (symmetric unlike PD): Postural instability w/frequent falls. Gait freezing occurs early in dz. Bradykinesia. Rigidity is axial > appendicular (unlike PD) w/retrocollis. Open, unblinking eyes (surprised look), masked facies, or blepharospasm & involuntary eye closure. Rarely w/pill-rolling rest tremor. Dystonia of extremities.
Visual: First sign is slowing of vertical saccades (initially overcome by VOR) then limited range. Horizontal saccades effected later. Nontargeted saccades (“look left/right”) affected first over targeted saccades (“look at my finger, then my nose”). Smooth pursuit slow w/saccadic intrusions. Eventually lose bell phenomena (closing eyelids causes eyes to roll up), convergence, and optokinetic nystagmus. Can have square-wave jerks & eyelid apraxia.
Bulbar sxs: Dysarthria (usually spastic, “growling” speech), dysphagia.
Cognitive: Executive dysfxn, reduced verbal fluency, perseveration. Apathy > disinhibition > dysphoria, anxiety. Depression. Pseudobulbar sx: emotional incontinence. “Applause sign”—preservation of automatic behavior (perseverative clapping). Palilalia—repetition of words.
Other (less common) features: Pyramidal symptoms, insomnia
Imaging: MRI w/atrophy of the midbrain may be seen; “Mickey Mouse sign” demonstrates atrophy on axial midbrain cuts; beaked “hummingbird” appearance of the midbrain on midsagittal view.
Rx: l-dopa: Some pts (<50%) have short-lived, moderate benefit. Amantadine (100 mg bid) may have slight benefit, helps drooling and dyskinesias. Botulinum: For dystonia. Multidisciplinary approach: PT/OT/social services.
CORTICOBASAL DEGENERATION (CBD)
Introduction: Progressive dz w/asymmetric parkinsonism and cortical/cognitive dysfxn. Prevalence ˜1/100 K but possibly accounts for up to 6% of parkinsonism. Onset >60 yo (possible female predominance).
Pathology: Frontoparietal atrophy + substantia nigra degeneration. Tauopathy w/neuronal neurofibrillary tangles (tau deposits), astrocyte tau plaques. “Balloon” neurons, neuronal achromasia (lack of staining).
Clinical features
Motor: Often asymmetric, usually starts in one arm. Parkinsonism: Bradykinesia, rigidity, tremor (often faster [6-8 Hz] than in PD and jerky), myoclonus (may be stimulus sensitive), postural instability (late in dz), gait short & shuffling. Dystonia: Present in most pts, asymmetric, painful; progresses to “dystonic clenched fist” (dystonic flexed hand, held in a fist, fingers clenched around adducted thumb). Dysarthria, dysphagia.
Cortical dysfxn: Asymmetric ideomotor apraxia (i.e., cannot imitate symbolic gestures such as tool use). Alien limb phenomenon → limb moves on its own accord, pt unaware of it, can interfere w/voluntary mvmt, limb may grasp objects + not release them. Cortical sensory loss (e.g., agraphesthesia; not primary sensory). Neglect.
Cognition: Dementia may be presenting (or only) sign (some CBD do not develop movement sxs). Nonfluent aphasia common (overlap w/FTLD). Depression, apathy, irritability.
Eye movements: Difficulty initiating saccades (horizontal, unlike PSP); once initiated, saccades are nl. Smooth pursuit slow w/saccadic intrusions.
Imaging: MRI nl early in dz, then asymmetric posterior frontal & parietal cortical atrophy. Dopamine transporter SPECT: Abnl unlike other dementias (AD), but this is abnl in other Parkinson-plus syndromes as well.
Rx: L-dopa: Response usually poor, transient. Tremor: beta-blocker, benzodiazepine, primidone. Dystonia: benzodiazepines, botulinum. Dementia: cholinesterase inhibitors unhelpful (probably because basal forebrain cholinergic neurons not involved in dz).
Dysphagia: Important late sx, PEG may be needed.
OTHER HYPOKINETIC MOVEMENT DISORDERS
